Tuberculosis (TB) infection is the leading cause of death in the setting of the Acquired Immune Deficiency Syndrome (AIDS). In the human immunodeficiency virus-1 (HIV-1)/TB co-infected host, the pathogenesis and outcome of each infection is greatly influenced by the other. Of the at least 11 subtypes or clades of the major (M) group of HIV-1 strains responsible for the current pandemic, the original clade or subtype isolated, B, has been the most studied. The C and E subtypes, however, are currently the most prevalent globally, accounting for approximately 50% and 30% of all new infections, respectively, and are the most prevalent in those areas of the world also most heavily burdened with TB, Africa and Asia. Notably, there are molecular differences between the B, C, and E subtypes, including distinct long terminal repeat (LTR) sequences. HIV- 1 gene expression, replication, transmission, and ultimately disease progression involves LTR activation, and it has been suggested that clade specific differences in LTR sequences may account for the disproportionate spread of subtypes C and E. Different clinical isolates of the causative agent of TB, Mycobacterium tuberculosis, (MTb) also have different phenotypes with respect to their ability to infect, cause disease and elicit cytokine responses including different levels of the cytokine tumor necrosis factor (TNF). TNF is involved in both the containment of TB disease in the latently infected host and in stimulating HIV-1 replication. Thus, characterization of the regulation of distinct HIV-1 subtypes and their interaction with MTb and differential host production of TNF and other cytokines is critical to the understanding of the pathogenesis of co-infection. Our overarching hypothesis is that HIV-1 isolates are regulated in a clade specific manner by distinct MTb strains via monocytic and T cell host responses to co-infection. In Aim 1, we will test the hypothesis that MTb regulates LTR-mediated HIV-1 transcription in a subtype-specific manner via the recruitment of distinct sets of cellular activators and chromatin remodeling. In Aim 2, we will investigate the mechanism by which MTb clinical isolates with different immunomodulatory properties regulate cytokine and chemokine receptor production and HIV-1 replication. This will also involve the identification of immune signatures in donor peripheral blood mononuclear cells infected with MTb isolates with different immunomodulatory properties and HIV-1. We anticipate that this proposal will result in contributions to our understanding of the basic mechanisms involved in subtype-specific HIV-1 replication by MTb and that it will provide insight MTb strain variation upon both HIV-1 and cytokine regulation. The long range goal of these studies is to identify subtype-specific transcriptional targets to inhibit HIV-1 replication in the setting of MTb infection and/or T cell activation secondary to MTb specific host immune responses.